Metformin: A Candidate Drug for Renal Diseases

Abstract

Over the past decades metformin has been the optimal first-line treatment for type 2 diabetes mellitus (T2DM). Only in the last few years, it has become increasingly clear that metformin exerts benign pleiotropic actions beyond its prescribed use and ongoing investigations focus on a putative beneficial impact of metformin on the kidney. Both acute kidney injury (AKI) and chronic kidney disease (CKD), two major renal health issues, often result in the need for renal replacement therapy (dialysis or transplantation) with a high socio-economic impact for the patients. Unfortunately, to date, effective treatment directly targeting the kidney is lacking. Metformin has been shown to exert beneficial effects on the kidney in various clinical trials and experimental studies performed in divergent rodent models representing different types of renal diseases going from AKI to CKD. Despite growing evidence on metformin as a candidate drug for renal diseases, in-depth research is imperative to unravel the molecular signaling pathways responsible for metformin’s renoprotective actions. This review will discuss the current state-of-the-art literature on clinical and preclinical data, and put forward potential cellular mechanisms and molecular pathways by which metformin ameliorates AKI/CKD.

Vitamins D and E Stimulate the PI3K-AKT Signalling Pathway in Insulin-Resistant SK-N-SH Neuronal Cells

“…The hypothetical evidence of insulin signalling dysregulation affecting hyper-phosphorylated AD markers by treating the hyperinsulin SK-N-SH cells with vitamins D and E was also validated. The chronic insulin resistance model shows significant suppression of AKT phosphorylation, suggesting the impairment of proteins in insulin signalling cascade pathways [57]. Clearly, the effect of vitamins D and E on increasing AKT phosphorylation has a high potency to restore insulin sensitization similar to the negative control (Figure 4).…”

Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

“…Apart from its glucose-lowering effect, metformin was studied for its cardioprotective and vasculo-protective effects and more recently for its effects as a cancer preventive and anti-cancer/anti-tumor agent in different cancers (Figure 1) [5,20,21]. Depending on patient prolife and various disease conditions or stages, metformin treatment-associated beneficial effects in the treatment of hepatic diseases [22][23][24][25], renal damage and disorders [26], neurodegenerative diseases [27][28][29], and bone disorders [30] were reported. In addition, metformin treatment-related antiaging effects, delay in the onset of age-related disorders, and improvement in longevity (lifespan) were reported in C. elegans, insects, and rodents [31][32][33][34].Interest has grown in studying the possible use of metformin as an anti-cancer/anti-tumor agent individually or in combination with frequently used chemotherapeutic agents and/or radiation.…”

Metformin and cardiorenal outcomes in diabetes: A reappraisal

“…Experimental studies are increasing understanding of the potential renoprotective effects of metformin. A recent review highlighted potentially beneficial renal mechanisms of metformin, especially signalling through the AMP kinase (AMPK)/mTOR pathway, reduction of endoplasmic reticulum stress, modulation of endothelial to mesenchymal transition, promotion of autophagy to clear away damaged cells and organelles, inhibition of reactive oxygen species and inflammation and oxidation caused by advanced glycation end products, and reduced lipoxicity . A decline in the activity of AMPK parallels the development of structural and functional abnormalities in the kidneys of mice with experimental CKD, and metformin treatment has been shown to reverse early changes of this type by restoring AMPK activity .…”